IMPACT-FH Study for Implementing Innovative Family Communication and Cascade Testing Strategies for Familial Hypercholesterolemia

Background Relatives of probands diagnosed with familial hypercholesterolemia (FH) should undergo cascade testing for FH. Objectives The purpose of this study was to evaluate probands’ choices of innovative strategies to communicate their FH result with relatives and facilitate cascade testing uptake. Methods Probands with an FH genetic result from the MyCode Community Health Initiative could choose to share their FH result with adult blood relatives via the Family and Healthcare Professional Packet (packet), family sharing and cascade chatbots (chatbot), and/or FH Outreach and Support Program (direct contact). Cascade testing uptake was measured as reported completion of genetic or cholesterol testing. Generalized estimating equations models were used to identify factors associated with testing. Results One hundred seventy five probands received an FH result, median age was 58.9 (IQR: 44.9-69.3), and 58.9% were female. Probands shared information about 1,915 adult and 163 minor relatives (11.9 relatives per proband). Seventy percent of probands (121/175) selected at least one strategy for at least one adult relative. An average of 1.2 strategies was selected per adult relative. Cascade testing was completed for 26.6% (144/541) of adults with at least one strategy selected, 2.4% (33/1,374) of adults without a strategy selected, and 25.2% (41/163) of minor relatives. Factors associated with increased cascade testing uptake were selection of at least one strategy (6.32 higher odds), specifically, selection of direct contact (16.78 higher odds). Conclusions Strategies implemented improved FH cascade testing uptake compared to previous estimates and in families where no strategy was selected. Overall uptake remains insufficient, which can be attributed to probands reluctance to select a strategy for many relatives.

The median age of FH patients in MyCode is 61 years, providing an opportunity for cascade testing of at least two generations of at-risk individuals in many families.Based on the data collected in 2018 for MyCode on 114 FH probands, there were 401 reported living first-degree relatives (FDRs) or 3.5 FDRs per FH proband.In that group (unpublished data), only 14 atrisk relatives from 6 FH families had completed cascade genetic testing (3.5%).These preliminary findings demonstrated the significant need for strategies to improve cascade testing uptake for FH families to benefit from the results of population screening for FH.
While there is support from payers, public health officials, and clinicians regarding the importance of cascade testing, how best to inform relatives of risk and implement cascade testing has yet to be determined. 12Novel implementation strategies for probands to communicate genetic risk with relatives have been developed but require further testing to assure generalizability. 13These strategies should provide education, offer support, and provide calls to action to assist probands and relatives in understanding their risk and empowering them to act. 14spite success in other countries with innovative approaches to inform relatives of FH risk, these strategies have not been tested for effectiveness or acceptability in the U.S. 6,15,16 We have previously reported on the development of implementation strategies for cascade testing informed by health communication theory and implementation science to improve cascade testing. 17ese strategies include the following: 1) Family and Healthcare Professional Packet (packet); 2) Family Sharing Chatbot (FSC) and Cascade Chatbot (CC); and/or 3) FH Outreach and Support Program (direct contact). 17In this study, we offered these innovative strategies to probands with FH to evaluate proband choice for family communication with the aim of improving cascade testing uptake.

METHODS STUDY DESIGN.
A prospective pragmatic study utilizing implementation strategies to improve family communication and cascade testing for FH was conducted as part of the IMPACT-FH ('Identification Methods, Patient Activation, and Cascade Testing for FH') study (Central Illustration ). 18Figure 1 highlights the pragmatic design of the IMPACT-FH trial using the nine specified domains using the PRECIS-2 tool. 19ese domains were scored by the study team.Higher scores reflect the extent to which the IMPACT-FH study was implemented in real-world practices.
Further details on the scoring from very explanatory to very pragmatic of the nine domains and rationale are available in Supplemental Table 1.The trial was conducted at Geisinger from July 2021 to April 2023.STUDY SETTING.This study relies on previous genomic health efforts at Geisinger including MyCode and the MyCode GSC program. 20,21MyCode is a biobank of serum, blood, and DNA samples for health discovery research from patient-participants that have also undergone exome sequencing.MyCode launched in 2007 and began returning clinically actionable results to participants and their healthcare clinicians in 2015. 20,21When a pathogenic or likely pathogenic (P/LP) variant is identified in MyCode, the variant is confirmed in a CLIA-certified genetics laboratory prior to clinical report return. 22The standard clinical process is for the MyCode GSC program to return results to patient-participants (defined as the proband for this study) and their clinicians in the electronic health record. 11Upon return in the standard process, probands receive a packet that includes    relatives to order a mail-in genetic testing kit for a fee ($20) within a 150-day window.This window is not specific to the chatbot or this study; it is the window set by the genetic testing laboratory for all "free" cascade testing available to relatives.If the packet or CC were chosen for a relative, sharing of these materials by the proband was voluntary and served as their HIPAA authorization.

An overview of the study timeline is shown in
Direct contact involves a genetic counselor with expertise in FH calling a relative and/or the relative's clinician to discuss the FH result, importance of cascade testing, and navigating them through testing, if desired.The study staff coached the proband to give their relatives a "heads-up" about direct contact.
The proband was asked if they wanted their relative(s) contacted directly by a genetic counselor, their relative's clinician contacted by the study staff (so their clinician could forward this information to their relative), or both.If the genetic counselor was to contact the relative directly, a "primer" letter was also sent to the relative prior to the direct contact via mail, secure email, or the patient electronic health portal (if the relative also received care at Geisinger).This primer also allowed the relative to opt-out of further contact by the study team.In this situation, the study team recontacted the proband and offered the option to authorize the sharing of their FH genetic test result with their relative's clinician instead.
When direct contact was chosen, genetic counselors were given authorization by the proband to share their information with their relatives or their relative's clinicians via a verbal HIPAA authorization.
PROBAND ELIGIBILITY.Probands had to be 18 years or older with a clinically confirmed P/LP genetic variant for FH in either LDLR, APOB, or PCSK9, which was returned to them by a genetic professional from July 1, 2021 to April 1, 2022 through the MyCode GSC program.FH results were disclosed per MyCode's standard clinical process to inform participants of their FH risk variant, described above. 11To be included, probands had to have a preferred language of English, provide information on at least one living   the FH result (Figure 2).The 1-month follow-up contact offered an additional opportunity to begin or expand upon the proband's strategy choices for each adult relative, the relative's information, and offered additional packets or to re-send the FSC/other materials as needed/requested.At the 6-month follow-up, the study team collected proband-reported outcomes on family communication choices (which strategies were sent by the proband) and cascade testing uptake.The proband was encouraged to select an alternative strategy for adult relatives that remained untested.For example, if the proband chose to use direct contact for an adult relative and testing was not performed by 6 months, then the proband would be offered the FSC/CC or packet for that relative at 6 months, and cascade testing uptake would be measured at 12 months.At the 12-month follow-up and final touchpoint, no additional strategies could be selected, and the study team collected proband-reported outcomes on family communication, strategy use, and cascade testing uptake.
OUTCOMES.The study team documented all at-risk relatives identified by probands.Adult relatives were defined as all living blood relatives.FDRs were defined as relatives who were parents, full siblings, and adult children (age >18 years old).Minors were any relative less than the age of 18 years old.Family communication choice was defined as the selection of a strategy (packet, CC, or direct contact program) by the proband to share their result with their relatives and recording of the strategy or strategies selected.
Cascade testing was defined as relatives completing either cholesterol and/or genetic cascade testing.
Cholesterol testing was reported to the study team at one of the study follow-ups or reported by the proband or relative during an interview with the study team.For Pennsylvania resident relatives, options for  2).
At study follow-ups, probands reported on strategies sent to relatives and uptake of cascade testing.
FAMILY COMMUNICATION STRATEGY.Of the 175 probands, 121 (69.1%) selected at least one strategy for at least one adult relative with a total of 663 strategies selected for 541 relatives; an average of 1.2 strategies was selected per relative.Packets were selected for 428, CCs for 188, and direct contact for 47 relatives (Supplemental Table 2).An average of 3.2 relatives per proband had a strategy selected.Most often, the proband selected the strategy for the relative at one of the study follow-ups.1.4-3.4),P ¼ 0.0008; and for direct contact 2.74 (95% CI:1.7-4.4),P < 0.0001 versus none selected).
Jones et al

IMPACT-FH Cascade Testing Program Results
Older age significantly impacted strategy selected by proband (P ¼ 0.01).Selection of the packet and direct contact significantly differed in relative's age from the no strategy selected (P ¼ 0.002 and      TRANSLATIONAL OUTLOOKS 2: Cascade testing programs should be personalized for every family and there is not a one-size-fits all approach and additional strategies should be investigated to help facilitate this conversation.
rangeThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.Manuscript received May 1, 2024; revised manuscript received June 11, 2024, accepted June 18, 2024.
information about their result and a 'Dear Family' letter to share with at-risk relatives.They are also provided the option to receive a link to the FSC, a HIPAA-compliant web-based conversational tool that probands can utilize to send a separate CC link to their relatives.The CC provides relatives with information about the result in the family and contact information for the GSC team should they wish to schedule an appointment for cascade testing.DESCRIPTION OF IMPLEMENTATION STRATEGIES.
Probands could choose different strategies for different relatives, and probands could choose different strategies at the different follow-up points.The optimized packet contains information about the proband's FH result, including a personalized cover letter to the relative, describing the FH result and what it means for the relatives.It also includes detailed instructions on how to pursue both genetic and cholesterol-based cascade testing, a letter relatives can share with their own clinician, and the proband's laboratory report containing the FH genetic result.The FSC is a proband-facing chatbot that explains why communicating the FH result to family is important and allows probands to share a CC link to at-risk relatives.The CC is a relative-facing chatbot that provides relatives with detailed information about FH and the importance of cascade testing and includes a genetic testing ordering module, allowing CENTRAL ILLUSTRATION IMPACT-FH Cascade Testing Program Jones LK, et al.JACC Adv.2024;3(9):101198.

FIGURE 1
FIGURE 1 PRagmatic-Explanatory Continuum Indicator Summary 2 Wheel for the IMPACT-FH Cascade Testing Program

FIGURE 2
FIGURE 2 Program Flow From FH Result Disclosure, to Strategy Selection, and to Study Follow-Up Visits J A C C : A D V A N C E S , V O L . 3 , N O .9 , 2 0 2 4 Jones et al S E P T E M B E R 2 0 2 4 : 1 0 1 1 9 8 IMPACT-FH Cascade Testing Program Results

FIGURE 3
FIGURE 3 Venn Diagram Showing Methods and Outcomes of Cascade Testing Uptake by Communication Strategy Utilized by the Relative

7.
Ademi Z, Watts GF, Pang J, et al.Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia. J Clin Lipidol.2014;8:390-400.

8.
Lázaro P, Pérez de Isla L, Watts GF, et al.Costeffectiveness of a cascade screening program for the early detection of familial hypercholesterolemia. J Clin Lipidol.2017;11:260-271.hypercholesterolemia, implementation strategies APPENDIX For supplemental tables, please see the online version of this paper.PERSPECTIVES COMPETENCY IN INTERPERSONAL & COMMUNICATION SKILLS: It is important to offer choice of strategies to probands to facilitate communication of FH results with relatives.TRANSLATIONAL OUTLOOK 1: When the FH Outreach and Support Program was selected, it had the highest odds of relatives undergoing cascade testing but how this program can be scaled and its cost require further investigation.

TABLE 1
Optimized Implementation Strategies for the IMPACT-FH Cascade Testing Program FH ¼ familial hypercholesterolemia; HCP ¼ healthcare professional.

TABLE 2
Demographics of Probands and Relatives a Values are median (IQR), n (%), or n. a Includes Asian, Black or African American or prefer not to answer.b Includes Hispanic or Latino or prefer not to answer.testing, 46.4% (32/69) had a positive result; of the 48 FACTORS ASSOCIATED WITH CASCADE TESTING UPTAKE.When any strategy was selected for adult Abul-Husn N, Manickam K, Jones LK, et al.Genetic identification of familial hypercholesterolemia within a single U.S. health care system.Science.2016;354:aaf7000.2. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG.Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.J Clin Endocrinol Metab.2012;97: 3956-3964.3. Wald DS, Bestwick JP, Morris JK, et al.Childparent familial hypercholesterolemia screening in primary care.N Engl J Med. 2016;375:1628-1637.Lee C, Rivera-Valerio M, Bangash H, et al.New case detection by cascade testing in familial hypercholesterolemia: a systematic review of the literature.Circ Genom Precis Med.2019;12: e002723. 1.